Myelin basic protein (MBP) and proteolipid protein (PLP) are major proteins of compact CNS myelin, whereas myelin-associated glycoprotein (MAG) and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) are mainly localized in associated oligodendroglial membranes. These 4 myelin proteins are differently affected in various dysmyelinating, demyelinating and remyelinating circumstances, and information about changes in these proteins can increase our understanding of the specific molecular processes going on in each individual disease. In most hypomyelinating mutant animals, MBP and PLP are decreased more than MAG and CNP, due to a greater deficiency of compact myelin then of associated oligodendroglial membranes. This is true regardless of the primary cause of the hypomyelination, e.g., a PLP gene defect (Shaking pup), a cholesterol storage disorder (CSD mice), a congenital virus infection (Border disease in sheep) or in human patients with Niemann-Pick C disease. However, the TAIEP rat expressed decreased amounts of MAG compared to other myelin proteins, and the MAG in the younger animals had a higher MW when compared to age-matched controls, most likely due to an extended presence of the immature large isoform of MAG. In caprine beta-mannosidosis, MAG, CNP and PLP levels were equally decreased, but MBP was relatively spared. This might be due to the presence of large storage vesicles, which interfere with the protein transport of MAG, PLP and CNP, while MBP translation is at the site of insertion into the myelin. Biochemical and histological analysis of white matter biopsies from 2 young girls with a progressive leukodystrophy due to unknown causes, revealed all the characteristic myelin proteins and lipids, but at significantly decreased amounts. In multiple sclerosis (MS) there is preferential loss of MAG at the edges of the plaques. Much of the MAG remaining in MS tissue is in the form of dMAG, a proteolytic cleavage product formed by a myelin-associated, calcium activated neutral protease (calpain). The MAG loss in MS may be related to this protease. dMAG was also present in some patients with AIDS (see Z01 NS 02805-04 LMCN0. The MAG/dMAG conversion rate in incubated myelin, purified from different species, was greatest in human myelin, rapid in myelin from other primates, and substantially slower in myelin from lower mammals such as rodents. This suggests that dMAG formation may be relevant to human demyelinating diseases. It seems that the MAG/dMAG conversion rate in purified myelin is very sensitive to the Ca2+ concentration in the samples and the levels of some gangliosides. Purified human calpain incubated with purified human MAG degraded the MAG totally.